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Research

Synthetic Biology

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Synthetic Biology Overview

Heidelberg

The Synthetic Biology group focuses on the development of tools for precision perturbation and control of cellular processes in cells and animals. Our main research branches are:

  • Development of optogenetic tools for spatiotemporally confined genome perturbations and their adaptation to study genome regulation in mammalian cells.
  • The engineering of safe and efficient AAV-CRISPR vectors for gene therapy applications.
  • Harnessing AI & machine learning to rationalise and accelerate the computational design of proteins with selected functions.

We are embedded into a great network of collaboration partners in Heidelberg (Prof. Dr. Dirk Grimm, Dr. Kathleen Börner) and have multiple, ongoing national and international collaborations, e.g. with Bruno E. Correia at the EPFL, Lausanne, and Prof. Dr. Pam Silver at Harvard Medical School.

Topics

Engineering anti-CRISPR proteins for conditional activation of CRISPR-Cas9

Anti-CRISPR proteins are potent inhibitors of CRISPR effectors. We engineer light-switchable derivatives of natural anti-CRISPRs by embedding photosensor domains, most typically the light-oxygen-voltage 2 (LOV2) domain from Avena sativa, into Acr structures (Bubeck & Hoffmann et al., 2019; Mathony and Hoffmann et al., submitted). The resulting, chimeric inhibitors block Cas9 in the dark, but release its activity upon blue light irradiation. This approach which we named CASANOVA, for CRISPR-Cas activity switching by novel, optogenetic variants of anti-CRISPR proteins, facilitates light-dependent genome editing and epigenome editing and is used in our lab to study genome regulatory processes. While CASANOVA was initially limited to the S. pyogenes Cas9, we are currently extending this original strategy to other Cas9 orthologues and Cas12. We are also developing designer Acrs that outperform their natural counterparts with respect to inhibition potency (Mathony, Harteveld and Schmelas et al., bioRxiv, 2019).
P1_Light-dependent_genome_editing-01
Light-inducible genome editing with CASANOVA.

AAV-CRISPR vectors for gene therapy applications

One of our central aims is to support the clinical translation of the CRISPR technologies by developing safe and efficient AAV-CRISPR vectors (Senis et al., 2014). Towards this goal, we closely collaborate with Prof. Dr. Dirk Grimm at Heidelberg University clinics. We use synthetic biology approaches to create switches and circuits that confine Cas9 activity to selected cell types, e.g. by coupling Cas9 activity to the abundance of cell type-specific microRNAs (Hoffmann et al., 2019). We also combine wet lab experiments with mathematical modeling to fine-tune Cas9 activity to desired levels, thereby enabling the kinetic insulation of ON- and OFF-target editing events (Aschenbrenner & Kallenberger et al., 2020).
P2_Cell-specific_editing
Hepatocyte-specific genome editing.

Machine learning-guided protein design

By training neural networks on thousands of protein sequences and corresponding 3D protein structures, we aim at creating algorithms that can inform protein design (Upmeier zu Belzen et al., 2019). Applications range from the prediction of engineering hotspots to facilitate the development of switchable proteins to the re-design of enzymes and creation of immune “stealth” protein therapeutics. 
P3_Sensitivity_analysis-01
Deep learning-assisted prediction of engineering hotspots in proteins. 
Dominik_niopek_portrait_Quadrat_400x400

Dominik obtained a M.Sc. in Molecular Biotechnology at Heidelberg University. In 2016, he completed his PhD at the German Cancer Research Center and took over the Synthetic Biology group.

Dr. Dominik Niopek

Group leader at BioQuant-Zentrum

BioQuant-Zentrum BQ054
Im Neuenheimer Feld 267
69120 Heidelberg

Research Group

SyntheticBiology_GroupPicture

 

Mareike Daniela Hoffmann
Doctoral Student
BioQuant-Zentrum BQ054
BioQuant-Zentrum BQ054
69120 Heidelberg
mareike.hoffmann@bioquant.uni-heidelberg.de
Jan Mathony
Doctoral Student
69120 Heidelberg
mathony@stud.uni-heidelberg.de
Sabine Aschenbrenner
Technical Assistant
BioQuant-Zentrum BQ054
Im Neuenheimer Feld 267
69120 Heidelberg
s.aschenbrenner@dkfz-heidelberg.de
Felix Bubeck
Student
BioQuant-Zentrum BQ054
Im Neuenheimer Feld 267
69120 Heidelberg
f.bubeck@stud.uni-heidelberg.de
Michael Jendrusch
Student
BioQuant-Zentrum BQ054
Im Neuenheimer Feld 267
69120 Heidelberg
jendrusch@stud.uni-heidelberg.de
Stefan Holderbach
Student
BioQuant-Zentrum BQ054
Im Neuenheimer Feld 267
69120 Heidelberg
s.holderbach@stud.uni-heidelberg.de
Daniel Heid
Student
BioQuant-Zentrum BQ054
Im Neuenheimer Feld 267
69120 Heidelberg
heid.daniel@gmx.de

Publications

Aschenbrenner, S.*, Kallenberger, S.*, Hoffmann, M. D., Huck, A., Eils, R.§ & Niopek, D.§ (2020). Coupling Cas9 to artificial inhibitory domains enhances CRISPR-Cas9 target specificity. Science Advances, 6(6), doi:10.1126/sciadv.aay0187

 

Hoffmann, M. D., Aschenbrenner, S., Grosse, S., Rapti, K., Domenger, C., Mastel, M., Eils, R.§, Grimm, D.§ & Niopek, D.§ (2019). Cell-specific CRISPR-Cas9 activation by microRNA-dependent expression of anti-CRISPR proteins. Nucleic Acids Research, 47(13), doi:10.1093/nar/gkz271

 

Upmeier zu Belzen, J., Bürgel, T., Holderbach, S., Bubeck, F., Adam, L., Gandor, C., Klein, M., Mathony, J., Pfuderer, P. L., Platz, L., Przybilla, M., Schwendemann, M., Heid, D., Hoffmann, M. D., Jendrusch, M., Schmelas, C., Waldhauer, M., Lehmann, I., Niopek, D.§ & Eils, R.§ (2019). Leveraging implicit knowledge in neural networks for functional dissection and engineering of proteins. Nature Machine Intelligence 1, 225-235. doi: 10.1038/s42256-019-0049-9

 

Bubeck, F., Hoffmann, M. D., Harteveld, Z., Aschenbrenner, S., Bietz, A., Waldhauer, M. C., Börner, K., Fakhiri, J., Schmelas, C., Dietz, L., Grimm, D., Correia, B. E., Eils, R.§ & Niopek, D.§ (2018). Engineered anti-CRISPR proteins for optogenetic control of CRISPR/Cas9. Nature Methods. 15(11), 924-927, doi:10.1038/s41592-018-0178-9

 

Niopek, D., Wehler, P., Roensch, J., Eils, R.§ & Di Ventura, B.§ (2016). Optogenetic Control of Nuclear Protein Export. Nature Communication. 7. doi: 10.1038/ncomms10624

 

*these authors contributed equally

§corresponding author

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